WO2014096828A1 - Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide - Google Patents

Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide Download PDF

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Publication number
WO2014096828A1
WO2014096828A1 PCT/GB2013/053356 GB2013053356W WO2014096828A1 WO 2014096828 A1 WO2014096828 A1 WO 2014096828A1 GB 2013053356 W GB2013053356 W GB 2013053356W WO 2014096828 A1 WO2014096828 A1 WO 2014096828A1
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WO
WIPO (PCT)
Prior art keywords
formula
tablet
further aspect
formulation
pharmaceutical composition
Prior art date
Application number
PCT/GB2013/053356
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English (en)
French (fr)
Inventor
Noel Alan Weldon BAKER
Alpesh MISTRY
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=49998566&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014096828(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA2893480A priority Critical patent/CA2893480C/en
Priority to ES13821906T priority patent/ES2742400T3/es
Priority to AU2013366023A priority patent/AU2013366023B2/en
Priority to BR112015014200A priority patent/BR112015014200A2/pt
Priority to RU2015126345A priority patent/RU2674978C2/ru
Priority to UAA201506048A priority patent/UA115342C2/uk
Priority to CN201380065855.6A priority patent/CN104853750B/zh
Priority to MX2015008067A priority patent/MX368670B/es
Priority to KR1020157019620A priority patent/KR20150096787A/ko
Priority to JP2015548757A priority patent/JP6328138B2/ja
Priority to SG11201504769WA priority patent/SG11201504769WA/en
Priority to EP13821906.8A priority patent/EP2934494B1/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2014096828A1 publication Critical patent/WO2014096828A1/en
Priority to PH12015501389A priority patent/PH12015501389A1/en
Priority to CR20150320A priority patent/CR20150320A/es
Priority to IL239521A priority patent/IL239521A0/en
Priority to ZA2015/05197A priority patent/ZA201505197B/en
Priority to HK16100256.1A priority patent/HK1212229A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pharmaceutical/formulation chemistry.
  • the invention is understood to apply generally to formulations of compounds which contain an increased percent loading of the active ingredient.
  • provided herein are formulations of N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5- dimethylpiperazin-l-yl]benzamide (Compound I) which exhibit satisfactory
  • the formulations are useful for treating of cancer.
  • Compound I is currently in clinical studies for the treatment of cancer, in particular cancers of the lung, breast, gatric and bladder. Dosing is currently done with orally delivered tablets with tablet strengths of 20 and lOOmg. These tablets exhibit satisfactory dissolution across the physiological pH range.
  • the manufacturing process used for clinical batches cannot be operated at commercial scale, due to a high incidence of filming which cannot be corrected using conventional means. It is desirable, therefore, to produce new pharmaceutical formulations of Compound I which overcome at least in part the above problems.
  • This invention is generally directed to formulations of compounds with improved manufacturability, in particular to formulations which contain an alkaline effervescent excipient and which exhibit satisfactory dissolution across the physiological pH range.
  • the compound of Formula (I) is a base and exhibits pH dependent solubility, having a solubility in simulated gastric fluid (pH1.2) of approximately 5mg/mL ('slightly soluble', using the definition given in the United States Pharmacopeia / National
  • alkaline effervescent excipients were effective in both improving the rate and extent of dissolution at low pH, despite the reduction in solubility under alkaline conditions, and in ameliorating the "filming" issues.
  • a further unexpected finding was that the use of an alternative lubricant, glyceryl dibehenate, was effective in ameliorating chemical degradation.
  • this invention is directed at least in part to the unexpected result that the use of an alkaline effervescent excipient with Formula (I) in the formulation allows the manufacture of tablets with improved manufacturability and / or a satisfactory dissolution across the physiological pH range; and, at least in part, to the unexpected result that an alternative lubricant allows the manufacture of tablets with improved stability.
  • this invention provides the use of an alkaline effervescent excipient with Formula (I) in the formulation allowing the manufacture of tablets with improved manufacturability and/or a satisfactory dissolution across the physiological pH range.
  • this invention provides the use of magnesium carbonate with Formula (I) in the formulation allowing the manufacture of tablets with improved manufacturability and/or a satisfactory dissolution across the physiological pH range.
  • this invention provides the use of calcium carbonate with Formula (I) in the formulation allowing the manufacture of tablets with improved manufacturability and/or a satisfactory dissolution across the physiological pH range.
  • this invention provides the use of sodium bicarbonate with Formula (I) in the formulation allowing the manufacture of tablets with improved manufacturability and/or a satisfactory dissolution across the physiological pH range.
  • this invention provides the use of an alternative lubricant with Formula (I) in the formulation allowing the manufacture of tablets with improved stability.
  • this invention provides the use of glyceryl dibehenate with Formula (I) in the formulation allowing the manufacture of tablets with improved stability.
  • a pharmaceutical composition comprising greater than 10% w/w of Formula (I) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition in unit dosage form comprising from 10 mg to 200 mgof Formula (I) (for example 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170mg, 180mg, 190mg or 200mg) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients.
  • 10 mg to 200 mgof Formula (I) for example 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170mg, 180mg, 190mg or 200mg
  • an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution
  • each of the previous integers represents a separate and independent aspect of the invention.
  • a unit dosage form of the pharmaceutical composition comprises between about lOmg to about 160 mg of Formula (I).
  • a unit dosage form of the pharmaceutical composition comprises between about 10 mg to about 140 mg of Formula (I).
  • a unit dosage form of the pharmaceutical composition comprises between about lOmg to about 130 mg of Formula (I).
  • a unit dosage form of the pharmaceutical composition comprises between about 15 mg to about 110 mg of Formula (I).
  • a unit dosage form of the pharmaceutical composition comprises 20 mg ⁇ 1 mg of Formula (I).
  • composition comprises 80 mg ⁇ 4 mg of Formula (I).
  • composition comprises 100 mg ⁇ 5 mg of Formula (I).
  • composition comprises 160 mg ⁇ 8 mg of Formula (I).
  • composition comprises 200 mg ⁇ 10 mg of Formula (I).
  • the pharmaceutical composition comprises between 10% w/w to 60% w/w of Formula (I).
  • the pharmaceutical composition comprises between 15% w/w to 50% w/w of Formula (I).
  • the pharmaceutical composition comprises between 15% w/w to 45%) w/w of Formula (I).
  • the pharmaceutical composition comprises between 15%> w/w to 40%) w/w of Formula (I).
  • the pharmaceutical composition comprises between 15%> w/w to 25%) w/w of Formula (I).
  • the pharmaceutical composition comprises about 20% w/w of Formula (I).
  • the pharmaceutical composition comprises 21.33% ⁇ 5% w/w of Formula (I).
  • the pharmaceutical composition comprises between 20.26%> w/w to 22.40% w/w of Formula (I).
  • the pharmaceutical composition comprises from 1%) w/w to 50% w/w of an alkaline effervescent excipient
  • the pharmaceutical composition comprises from 1%) w/w to 40% w/w of an alkaline effervescent excipient
  • the pharmaceutical composition comprises from 10%> w/w to 30%) w/w of an alkaline effervescent excipients.
  • the pharmaceutical composition comprises about 20% w/w of an alkaline effervescent excipients.
  • the pharmaceutical composition comprises from 15%> w/w to 20%) w/w of an alkaline effervescent excipients.
  • the pharmaceutical composition comprises less than or equal to 6%> w/w of a conventional lubricant
  • the pharmaceutical composition comprises less than or equal to 5% w/w of an alternative lubricant
  • the pharmaceutical composition comprises less than or equal to 4% w/w of an alternative lubricant
  • the pharmaceutical composition comprises less than or equal to 3% w/w of an alternative lubricant.
  • the pharmaceutical composition comprises between 0.25% w/w and 8% w/w of an alternative lubricant.
  • the pharmaceutical composition comprises between 0.5% w/w and 5% w/w of an alternative lubricant.
  • the pharmaceutical composition comprises between 1% w/w and 4% w/w of an alternative lubricant.
  • the pharmaceutical composition comprises between 2.5% w/w and 3.5% w/w of an alternative lubricant.
  • the pharmaceutical composition comprises about 3% w/w of an alternative lubricant.
  • a pharmaceutical composition comprising greater than 10% w/w of Formula (I) and less than or equal to 50% w/w of an alkaline effervescent excipient ; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition comprising greater than 15% w/w of Formula (I) and less than or equal to 40% w/w of an alkaline effervescent excipient ; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition comprising greater than 15% w/w of Formula (I) and less than or equal to 30% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition comprising greater than 15% w/w of Formula (I) and less than or equal to 20% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition comprising from 10% w/w to 50%>w/w of Formula (I) and from 1%> w/w to 50% w/w of an alkaline effervescent excipient ; and optionally further comprising one or more
  • a pharmaceutical composition comprising from 15%> w/w to 35% w/w of Formula (I) and from 10%> to 40% w/w of an alkaline effervescent excipient ; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition comprising from 15%> w/w to 25% w/w of Formula (I) and from 15% w/w to 25% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • a pharmaceutical composition comprising about 20% w/w of Formula (I) and about 20% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • a unit dosage form comprising from 15%) w/w to 45% w/w of Formula (I) and from 10% to 40% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the unit comprises from 10 to 200 mg of Formula (I)
  • a unit dosage form comprising from 15%) w/w to 40% w/w of Formula (I) and from 10% to 40% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the unit comprises from 10 to 200 mg of Formula (I).
  • a unit dosage form comprising from 15%) w/w to 25% w/w of Formula (I) and from 15% to 25% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the unit comprises 20 mg of Formula (I).
  • a unit dosage form comprising from 15%) w/w to 25% w/w of Formula (I) and from 15% to 25% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the unit comprises 80 mg of Formula (I).
  • a unit dosage form comprising from 15% w/w to 25% w/w of Formula (I) and from 15% to 25% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the unit comprises 160 mg of Formula (I).
  • optional ingredients which can be added to the pharmaceutical composition include one or more of the following:
  • composition may optionally include one or more of the following:
  • fillers which, when employed, range between for example about 10 to about 75 weight percent (e.g. about 15 to about 70 weight percent) of the remainder of the dry formulation;
  • binding agents which, when employed range between for example about 2 to about 8 weight percent of the remainder of the dry formulation
  • lubricants which, when employed, range from between about 0.25 and 5 weight percent of the remainder of the dry formulation
  • disintegrants which, when employed, range from between about 0.5 and 10.0 weight percent (e.g. about 5 weight percent) of the remainder of the dry formulation.
  • the pharmaceutical composition further comprises one or more additional ingredients independently selected from, for example a) fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c or Pearlitol 160c) or microcrystalline celluloses (e.g. MCC Avicel PH 101, Emcocel 90M, etc.); b) binding agents such as Plasdone K29/32, Povidone, microcrystalline celluloses or Kollidon K30;
  • fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c or Pearlitol 160c) or microcrystalline celluloses (e.g. MCC Avicel PH 101, Emcocel 90M, etc.);
  • binding agents such as Plasdone K29/32, Povidone, microcrystalline celluloses or Kollidon K30;
  • lubricants such as glyceryl dibehenate
  • disintegrants such as sodium starch glycolate, for example ExploTab or Glycolys LV.
  • a pharmaceutical composition comprising from 15% w/w to 25% w/w of Formula (I), from 15% w/w to 25% w/w of an alkaline effervescent excipients, from 2.5% w/w to 3.5% w/w of an alternative lubricant; and further comprising from 40% w/w to 60% filler w/w, from 1% w/w to 3% w/w binder and 5% w/w to 9% w/w disintegrant.
  • a tablet comprising greater than 10%) w/w of Formula (I) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients.
  • a tablet comprising from lOmg to 200 mg of Formula (I) (for example 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170mg, 180mg 190mg or 200mg) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more
  • each of the previous integers represents a separate and independent aspect of the invention.
  • the tablet comprises between about 10 mg to about 160 mg of Formula (I).
  • the tablet comprises between about 10 mg to about 140 mg of Formula (I).
  • the tablet comprises between about lOmg to about 130 mg of Formula (I).
  • the tablet comprises between about 15 mg to about 110 mg of Formula (I).
  • the tablet comprises 20 mg ⁇ 1 mg of Formula
  • the tablet comprises 80 mg ⁇ 4 mg of Formula (I).
  • the tablet comprises 100 mg ⁇ 5 mg of Formula (I). In a further specific aspect of the invention, the tablet comprises 160 mg ⁇ 8 mg of Formula (I).
  • the tablet comprises 200 mg ⁇ 10 mg of Formula (I).
  • the tablet comprises from 1% w/w to 50% w/w of an alkaline effervescent excipient
  • the tablet comprises from 1% w/w to 40% w/w of an alkaline effervescent excipient
  • the tablet comprises from 10% w/w to 30% w/w of an alkaline effervescent excipients.
  • the tablet comprises about 20% w/w of an alkaline effervescent excipients.
  • the tablet comprises 21.33% ⁇ 5% w/w of Formula (I).
  • the tablet comprises between 20.26% w/w to 22.40% w/w of Formula (I).
  • the tablet comprises between about 15% w/w to about 25% w/w of Formula (I).
  • the tablet comprises less than or equal to 50%) w/w of an alkaline effervescent excipient.
  • the tablet comprises less than or equal to 40% w/w of an alkaline effervescent excipient.
  • the tablet comprises less than or equal to 30% w/w of an alkaline effervescent excipient.
  • the tablet comprises less than or equal to 20% w/w of an alkaline effervescent excipient.
  • the tablet comprises less than or equal to 6% w/w of a conventional lubricant
  • the tablet comprises less than or equal to 5%) w/w of an alternative lubricant In a still further aspect of the invention, the tablet comprises less than or equal to 4% w/w of an alternative lubricant
  • the tablet comprises less than or equal to 3% w/w of an alternative lubricant.
  • the tablet comprises between 0.25% w/w and 8%o w/w of an alternative lubricant.
  • the tablet comprises between 0.5% w/w and 5%o w/w of an alternative lubricant.
  • the tablet comprises between 1%> w/w and 4%o w/w of an alternative lubricant.
  • the tablet comprises between 2.5% w/w and 3.5%) w/w of an alternative lubricant.
  • the tablet comprises about 3% w/w of an alternative lubricant.
  • a tablet comprising from 10%> w/w to 50%)w/w of Formula (I) and from 1%> w/w to 50% w/w of an alkaline effervescent excipient ; and optionally further comprising one or more pharmaceutically acceptable ingredients.
  • a tablet comprising from 15% w/w to 35%) w/w of Formula (I) and from 10% to 40% w/w of an alkaline effervescent excipient ; and further comprising one or more pharmaceutically acceptable ingredients.
  • a tablet comprising from 15% w/w to 25%) w/w of Formula (I) and from 15% w/w to 25% w/w of an alkaline
  • effervescent excipient and further comprising one or more pharmaceutically acceptable ingredients.
  • a tablet comprising about 20%) w/w of Formula (I) and about 20% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • a tablet comprising from 15% w/w to 45%) w/w of Formula (I) and from 10% to 40% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the tablet comprises from 10 to 200 mg of Formula (I)
  • a tablet comprising from 15% w/w to 40%) w/w of Formula (I) and from 10%> to 40% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the tablet comprises from 10 to 200 mg of Formula (I).
  • a tablet comprising from 15%> w/w to 25%) w/w of Formula (I) and from 15%> to 25% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the tablet comprises 20 mg of Formula (I).
  • a tablet comprising from 15%> w/w to 25%) w/w of Formula (I) and from 15%> to 25% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the tablet comprises 80 mg of Formula (I).
  • a tablet comprising from 15%> w/w to 25%) w/w of Formula (I) and from 15%> to 25% w/w of an alkaline effervescent excipients and further comprising one or more pharmaceutically acceptable ingredients, wherein the tablet comprises 160 mg of Formula (I).
  • the dosage forms of this invention may include one or more pharmaceutically acceptable excipients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings or colorants. It will be understood that an individual excipient may be multifunctional. Examples of one or more pharmaceutically acceptable excipients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings or colorants. It will be understood that an individual excipient may be multifunctional. Examples of
  • administered in accordance with the present invention will vary depending upon the particular active ingredient employed, the mode by which the active ingredient is to be administered, and the condition or disorder to be treated.
  • optional ingredients which can be added to make up the remainder of the tablet include one or more of the following: a) fillers which, when employed, range between for example about 10 to about 75 weight percent (e.g. about 15 to about 70 weight percent) of the remainder of the tablet formulation;
  • binding agents which, when employed range between for example about 2 to about 8 weight percent of the remainder of the tablet formulation
  • disintegrants which, when employed, range from between about 0.5 and 10.0 weight percent (e.g. about 5 weight percent) of the remainder of the tablet formulation.
  • the tablet further comprises one or more additional ingredients independently selected from, for example:
  • fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c or Pearlitol 160c) or microcrystalline celluloses (e.g. MCC Avicel PH 101, Emcocel 90M, etc.);
  • binding agents such as Plasdone K29/32, Povidone, microcrystalline celluloses or Kollidon K30;
  • lubricants such as glyceryl dibehenate
  • disintegrants such as sodium starch glycolate, for example ExploTab or
  • the tablet optionally further comprises a suitable coating, for example a film coating.
  • a coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation, or to modify or control the release of Formula (I) from the formulation.
  • the pharmaceutical composition comprises the following components by weight:
  • composition A (mg)
  • Composition B (mg)
  • the pharmaceutical composition comprises the following components (% w/w)
  • compositions A and B (%w/w)
  • the invention comprises a tablet formed from the pressing of composition A and/or composition B into tablet form.
  • Step A - comprises mixing Formula (I) with an alkaline effervescent excipient optionally in the presence of one or more pharmaceutically acceptable ingredients .
  • Step A is carried out in the presence of one or more additional fillers (such as mannitol) and optionally in the presence of one or more
  • Step A is carried out in the presence of one or more additional fillers (such as mannitol) and optionally in the presence of one or more binding agents and/or one or more disintegrants.
  • additional fillers such as mannitol
  • Step B - comprises adding purified water and/or binder solution into the powder mixture from Step A above and mixing to form granules and optionally passing through a filter screen to break-up agglomerates. In a further aspect between about 10% and 45% by weight of purified water is added into the powder mixture.
  • Step C - comprises drying the granules produced in Step B above until an LOD of less than 10% (e.g. less than 5%) is achieved, to provide dried granules.
  • Step D - comprises optionally milling the dried granules from Step C.
  • Step E - optionally, comprises mixing the milled granules from Step D with an alkaline effervescent excipient.
  • a process for the preparation of a pharmaceutical composition which process (wet granulation process) comprises:
  • Formula (I) a) blending Formula (I) with an effervescent agent , one or more additional fillers (such as mannitol) and optionally in the presence of one or more binding agents and/or one or more disintegrants and/or one or more other excipients; b) adding between about 10% and 45% by weight of purified water and/or binder solution into the powder mixture of a) above and mixing to form enlarged granules and optionally passing through a filter screen to break-up large agglomerates; and
  • Step A a process for the preparation of a pharmaceutical composition which process comprises the following steps Step A - mixing Formula (I) optionally with an alkaline effervescent excipient optionally in the presence of one or more pharmaceutically acceptable ingredients.
  • Step A is carried out in the presence of one or more additional fillers (such as mannitol) and optionally in the presence of one or more
  • Step A is carried out in the presence of one or more additional fillers (such as mannitol) and optionally in the presence of one or more binding agents and/or one or more disintegrants.
  • additional fillers such as mannitol
  • Step B comprises adding purified water and/or binder solution into the powder mixture from Step A above and mixing to form granules and optionally passing through a filter screen to break-up agglomerates. Typically, between about 10%> and 45%) by weight of purified water and/or binder solution is added into the powder mixture.
  • Step C - comprises drying the granules produced in Step B above until an LOD of less than 10% (e.g. less than 5%) is achieved, to provide dried granules.
  • Step D - comprises milling the dried granules from Step C to give milled granules
  • Step E - comprises mixing the milled granules from Step D with an effective amount of an alkaline effervescent excipient.
  • a process for the preparation of a pharmaceutical composition which process (wet granulation process) comprises:
  • mannitol and optionally in the presence of one or more binding agents and/or one or more disintegrants and/or one or more other excipients; b) adding between about 10% and 45% by weight of purified water and/or binder solution into the powder mixture of a) above and mixing to form granules and optionally passing through a filter screen to break-up agglomerates;
  • this invention further comprises milling the dried granules.
  • the dried granules are milled so that about 90 weight percent have a particle size between about 25 ⁇ to about 3500 ⁇ in diameter.
  • the dried, milled, granules are mixed with a conventional and/or alternative lubricant, and then the resulting pharmaceutical composition is tabletted.
  • Conventional and alternative lubricants include glyceryl dibehenate, sodium stearyl fumarate, magnesium stearate, colloidal silica and talc.
  • the alternative lubricant (such as glyceryl dibehenate) can be added to the dry granules prior to milling, and then the resulting pharmaceutical composition is milled and then tabletted.
  • this invention provides a wet granulated formulation comprising between 10% w/w to 60% w/w of Formula (I) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients.
  • the wet granulated formulation comprises between 15% w/w to 50% w/w of Formula (I).
  • the wet granulated formulation comprises between 15% w/w to 40% w/w of Formula (I).
  • the wet granulated formulation comprises between 15% w/w to 25%) w/w of Formula (I).
  • the wet granulated formulation comprises about 20% w/w of Formula (I).
  • the wet granulated formulation contains 21.33% ⁇ 5% w/w of Formula (I).
  • the wet granulated formulation comprises between 20.26% w/w to 22.40% w/w of Formula (I).
  • the wet granulated formulation comprises from 1%) w/w to 50% w/w of an alkaline effervescent excipient.
  • the wet granulated formulation comprises from 1% w/w to 40% w/w of an alkaline effervescent excipient.
  • the wet granulated formulation comprises from 10% w/w to 30%) w/w of an alkaline effervescent excipient
  • the wet granulated formulation comprises from 15% w/w to 25%) w/w of an alkaline effervescent excipient
  • the wet granulated formulation comprises about 20% w/w of an alkaline effervescent excipient
  • a wet granulation formulation comprising from 10% w/w to 50% w/w of Formula (I) and from 1% w/w to 50% w/w of an effervescent agent; and further comprising one or more pharmaceutically acceptable ingredients.
  • a wet granulation formulation comprising greater from 10% w/w to 45% w/w of Formula (I) and from 10% w/w to 45% w/w of an alkaline effervescent excipient; and further comprising one or more
  • a wet granulation formulation comprising from 15% w/w to 25% w/w of Formula (I) and from 15% to 25% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • a wet granulation formulation comprising about 20% w/w of Formula (I) and about 20% w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • the wet granulation formulation comprises Formula (I), water, an alkaline effervescent excipient , additional filler(s), binding agent(s) and disintegrant(s).
  • this invention provides a tablet formed by compressing the wet granulated formulation.
  • Step D a further process for the preparation of a pharmaceutical composition as defined above which process comprises passing the mixture of Step A above through a compactor to produce dry granules (Step D).
  • a process for the manufacture of a pharmaceutical composition which process (roller compaction process) comprises:
  • additional fillers such as mannitol
  • additional fillers such as mannitol
  • binding agents such as mannitol
  • disintegrants such as mannitol
  • this invention further comprises milling the dried granules.
  • the dried granules are milled so that about 90 weight percent have a particle size between about 25 ⁇ to about 3500 ⁇ in diameter.
  • the dried, milled, granules are mixed with a lubricant, and then the resulting pharmaceutical composition is tabletted.
  • Suitable lubricants include glyceryl dibehenate, sodium stearyl fumarate, magnesium stearate, colloidal silica and talc.
  • this invention further comprises milling the dried granules.
  • the dried granules are milled so that about 90 weight percent have a particle size between about 25 ⁇ to about 3500 ⁇ in diameter.
  • Formula (I) optionally with an alkaline effervescent excipient, one or more additional fillers (such as mannitol) and optionally in the presence of one or more binding agents and/or one or more disintegrants and/or one or more other excipients;
  • additional fillers such as mannitol
  • Suitable lubricants include glyceryl dibehenate, sodium stearyl fumarate, magnesium stearate, colloidal silica and talc.
  • the lubricant (such as glyceryl dibehenate) can be added to the dry granules prior to milling, and then the resulting pharmaceutical composition is milled and then tabletted.
  • this invention provides a roller compaction formulation comprising greater than 10% w/w of Formula (I) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients.
  • roller compaction formulation comprises between 10% w/w to 60% w/w of Formula (I). In a further aspect, the roller compaction formulation comprises between 15% w/w to 50%) w/w of Formula (I).
  • roller compaction formulation comprises between 15%> w/w to 45%o w/w of Formula (I).
  • roller compaction formulation comprises between 15%> w/w to 40%) w/w of Formula (I).
  • roller compaction formulation comprises between 15%> w/w to 25%) w/w of Formula (I).
  • roller compaction formulation comprises about 20%) w/w of Formula (I).
  • the roller compaction formulation contains 21.33% ⁇ 5% w/w of Formula (I).
  • roller compaction formulation contains 20.26%) w/w to 22.40% w/w of Formula (I).
  • the roller compaction formulation comprises from 1%> w/w to 50% w/w of an alkaline effervescent excipient.
  • the roller compaction formulation comprises from 1%> w/w to 40%o w/w of an alkaline effervescent excipient.
  • the roller compaction formulation comprises from 10%> w/w to 30%o w/w of an alkaline effervescent excipient.
  • the roller compaction formulation comprises from 15%> w/w to 25%o w/w of an alkaline effervescent excipient.
  • the roller compaction formulation comprises about 20% w/w of an alkaline effervescent excipient.
  • roller compaction formulation comprising from 15%> w/w to 45% of Formula (I) and from 10%> w/w to 40% w/w of an alkaline effervescent excipient; and further comprising one or more
  • roller compaction formulation comprising from 15% w/w to 25% w/w of Formula (I) and from 15% w/w to 25%o w/w of an alkaline effervescent excipient; and further comprising one or more pharmaceutically acceptable ingredients.
  • the roller compaction formulation comprises Formula (I), an alkaline effervescent excipient, additional filler(s), binding agent(s) and disintegrant(s).
  • this invention provides a tablet formed by compressing the roller compaction formulation.
  • a process for the manufacture of a pharmaceutical composition which process (direct compression process) comprises:
  • additional fillers such as mannitol and optionally in the presence of one or more binding agents and/or one or more disintegrants and/or one or more lubricants and/or one or more other excipients;
  • the direct compression formulation comprises Formula (I), an alkaline effervescent excipient, additional filler(s), binding agent(s), lubricant(s) and disintegrant(s).
  • this invention provides a tablet formed directly by compressing the mixture of (a) above.
  • this invention provides a direct compression formulation comprising greater than 10% w/w of Formula (I) and an amount of an alkaline effervescent excipient that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients.
  • the direct compression formulation comprises between 10% w/w to 60% w/w of Formula (I).
  • the direct compression formulation comprises between 10% w/w to 50% w/w of Formula (I).
  • the direct compression formulation comprises between 15% w/w to 40%) w/w of Formula (I).
  • the direct compression formulation comprises between 15%> w/w to 25%) w/w of Formula (I).
  • the direct compression formulation comprises about 20%) w/w of Formula (I). In a specific aspect of the invention, the direct compression formulation contains 21.33% ⁇ 5% w/w of Formula (I).
  • the direct compression formulation contains 20.26%) w/w to 22.40% w/w of Formula (I).
  • the direct compression formulation comprises from 1%> w/w to 50% w/w of an alkaline effervescent excipient.
  • the direct compression formulation comprises from 1%> w/w to 40%) w/w of an alkaline effervescent excipient.
  • the direct compression formulation comprises from 10%> to 30%) w/w of an alkaline effervescent excipient.
  • the direct compression formulation comprises from 15%> to 25%o w/w of an alkaline effervescent excipient.
  • the direct compression formulation comprises about 20% w/w of an alkaline effervescent excipient.
  • a direct compression formulation comprising from 10%> w/w to 50% w/w of Formula (I) and from 1%> w/w to 50%) w/w of an effervescent agent; and further comprising one or more pharmaceutically acceptable ingredients.
  • a direct compression formulation comprising froml5%> w/w to 45% w/wof Formula (I) and from 10% w/w to 40%) w/w of an effervescent agent; and further comprising one or more pharmaceutically acceptable ingredients.
  • a direct compression formulation comprising from 15% w/w to 25% w/w of Formula (I) and from 15% w/w to 25%o w/w of an effervescent agent; and further comprising one or more pharmaceutically acceptable ingredients.
  • the pharmaceutical composition and/or tablet and/or wet granulation formulation and/or roller compaction formulation and/or direct compression formulation can additionally and optionally include a colourant, as long as it is approved and certified by the FDA.
  • exemplary colours include allura red, acid fuschin D, napthalone red B, food orange 8, eosin Y, phyloxine B, erythrosine, natural red 4, carmine, red iron oxide, yellow iron oxide, black iron oxide, titanium dioxide and the like.
  • Sweetening agents can also be added to the pharmaceutical composition and/or tablet and/or wet granulation formulation and/or roller compaction formulation and/or direct compression formulation or to the the outer core of the tablet to create or add to the sweetness. Saccharide fillers and binders, e.g.
  • mannitol, lactose, and the like can add to this effect.
  • cyclamates, saccharin, aspartame, acesulfame K (Mukherjee (1997) Food Chem. Toxicol. 35: 1177-1179), or the like (Rolls (1991) Am. J. Clin. Nutr. 53 :872-878), can be used.
  • Sweeteners other than sugars have the advantage of reducing the bulk volume of the pharmaceutical composition and/or tablet (core tablet and/or coat) and/or wet granulation formulation and/or roller compaction formulation and/or direct compression formulation and not effecting the physical properties of the tablet.
  • the pharmaceutical composition and/or tablet and/or wet granulation formulation and/or roller compaction formulation and/or direct compression formulation can additionally and optionally be coated using a conventional pan coater.
  • the film coat may be applied by spraying an aqueous suspension of the coating ingredients onto the tablet cores.
  • an effervescent excipient refers to any pharmaceutically acceptable material which evolves a gas in response to a stimulus, for example the evolution of carbon dioxide on acidification.
  • An example of an effervescent excipient is a carbonate, for example a metal carbonate (such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or aluminium carbonate) or an organic carbonate (such as disodium glycine carbonate, dimethyl carbonate or ethylene carbonate).
  • a further example of an effervescent excipient is a bicarbonate, for example a metal bicarbonate (such as sodium hydrogen carbonate or potassium hydrogen carbonate).
  • alkaline refers to a material which induces an increase in pH when added to an aqueous system.
  • alkaline excipient refers to any pharmaceutically acceptable material which is alkaline, for example an inorganic base such as disodium hydrogen phosphate or sodium hydroxide.
  • an alkaline effervescent excipient is a pharmaceutically acceptable material having both effervescent activity and alkaline properties, for example sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium carbonate and sodium carbonate.
  • alkaline effervescent excipients referred to above represents a separate and independent aspect of the invention.
  • the alkaline effervescent excipient is selected from a metal carbonate or a metal bicarbonate.
  • the alkaline effervescent excipient is selected from magnesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or sodium carbonate.
  • the alkaline effervescent excipient is magnesium carbonate.
  • binding agent refers to a pharmaceutically acceptable compound or composition added to a formulation to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. Dry binders used for direct compaction must exhibit cohesive and adhesive forces so that when compacted the particles agglomerate. Binders used for wet granulation are hydrophilic and soluble in water and are usually dissolved in water to form a wet mass that is then granulated.
  • binding agents includes, but are not limited to, Povidone, Plasdone K29/32, Plasdone S-630, hydropropyl cellulose, methylcellulose, polyvinylpyrrolidone, aluminium stearate, hydroxypropylmethylcellulose and the like. It is possible for such binding agents to additionally act as water sequestering agents (e.g. Povidone).
  • filler refers to any pharmaceutically acceptable material or composition added to a formulation to add bulk. Suitable fillers include, but are not limited to, mannitol, lactose, microcrystalline cellulose, silified microcrystalline cellulose and dicalcium phosphate.
  • lubricant refers to any pharmaceutically acceptable agent which reduces surface friction, lubricates the surface of the granule, decreases tendency to build-up of static electricity, and/or reduces friability of the granules.
  • lubricants can serve as anti-agglomeration agents.
  • Conventional lubricants include stearic acid and related compounds such as magnesium stearate and sodium stearyl fumarate.
  • Alternative lubricants include glyceryl dibehenate, colloidal silica, talc, other hydrogenated vegetable oil or triglycerides. Examples of suitable alternative lubricants include, but are not limited to, glyceryl dibehenate.
  • disintegrant refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • disintegrants include, but are not limited to, non- saccharide water soluble polymers, such as cross-linked povidine.
  • Other disintegrants that can also be used include, e.g. croscarmellose sodium, sodium starch glycolate, and the like, e.g. see Khattab (1992) J. Pharm. Pharmacol. 45:687- 691.
  • drying and “dried” refer to a process which decreases the water content of a composition to a desired level.
  • compressing refers to the process of applying compressive force to a formulation (powder or granules), as within a die, to form a tablet.
  • compressed tablet and “pressed tablet” mean any tablet formed by such a process.
  • filming refers to the adhesion of material to tablet punch surfaces. If sufficient material is allowed to build on punch surfaces then, among other defects, tablet weights may reduce below acceptable limits. (Journal of Pharmaceutical Sciences, Vol. 93(2), 2004).
  • tablette is used in its common context, and refers to a solid composition made by compressing and/or molding a mixture of compositions in a form convenient for swallowing or application to any body cavity.
  • tablette strength is calculated based upon the amount of Compound
  • percent loading is calculated by reference to the percentage by weight of Compound I
  • low pH refers to a measured pH of less than 5, such as less than 3, for example between 0 and 3.
  • satisfactory in vitro dissolution refers to a percent dissolution of greater than or equal to 70% within 30 minutes in a suitable dissolution medium at 37°C ⁇ 0.5°C as measured using the general procedure of the United States Pharmacopeia (Apparatus 2).
  • stable formulation refers to a formulation which, following storage for 4 weeks at elevated temperature and humidity, such as 40°C and 75% relative humidity, exhibits water absorption of less than 10%, such as less than 5%, for example between 0 and 5%; and / or chemical degradation of less than 3%, such as less than 2.5 %, for example between 0 and 2.5%; and / or which exhibits satisfactory in vitro dissolution.
  • Figure 1 shows a plot of the percentage dissolution using pH1.3 hydrochloric acid / sodium chloride buffer of ten alternative tablet formulations.
  • Figure 2 shows a plot of the percentage dissolution using pH1.3 hydrochloric acid / sodium chloride buffer of a further nineteen alternative tablet formulations.
  • Figure 3 shows a plot of the percentage dissolution using pH6.8 phosphate buffer of five alternative tablet formulations in which the lubricant content was varied.
  • Figure 4 shows a plot of the percentage dissolution using pH1.3 hydrochloric acid / sodium chloride buffer for ten alternative tablet formulations in which Formula (I), magnesium carbonate and lubricant was varied.
  • Figure 5 shows a plot of the percentage dissolution using pH6.8 phosphate buffer for ten alternative tablet formulations in which Formula (I), magnesium carbonate and lubricant was varied.
  • API Activel Pharmaceutical Ingredient
  • CrosPov crospovidone
  • DCPA dicalcium Phosphate (anhydrous)
  • DCPD dicalcium Phosphate (dihydrate)
  • Glydb glyceryl dibehenate
  • HPC hydroxypropylcellulose
  • L-HPC hydroxypropylcellulose, low- substituted
  • MCC cellulose, microcrystaline
  • MgSt magnesium stearate
  • nm nanometer
  • JP Japanese Pharmacopeia 15 th Edition, English Version
  • PhEur European Pharmacopoeia 6 th Edition (Directorate for the
  • Table 1 shows materials used, pharmacopeial status, grade and supplier.
  • Table 2 below shows equipment used, model and supplier.
  • Example 1 Assessment of dissolution performance of ten alternative tablet forms
  • Formula (I) can change under certain conditions.
  • Formula (I) can convert from a crystalline powder to a highly viscous material under low pH and at high concentration (both conditions need to be met simultaneously). Theoretically, these conditions will be met in the microenvironment of the tablet matrix either using a low pH dissolution method (e.g. pH1.3) or in the stomach.
  • the relative surface area of Formula (I) reduces when the viscous material forms and this is associated with a reduced rate of solubilisation of Formula (I). This can be observed as a reduced rate of dissolution using a low pH method.
  • Run 1 is comparable to the Phase 1 clinical formulation and is the positive control.
  • Run 2 is a negative control as it contains a high concentration of Formula (I) and has no alkalising agent.
  • Run 5 tests Hypothesis I (Na 2 HP0 4 is an alkalising agent).
  • Runs 7, 9 and 10 test Hypothesis II (no alkalising agent, but varying disintegrants).
  • Runs 3, 4, 6 and 8 test both Hypotheses I and II (they contain carbonate/bicarbonate alkalizing agents which both increase the pH microenvironment and liberate carbon dioxide in acidic conditions; carbon dioxide liberation can help to disperse Formula (I)).
  • Formula (I) and the excipients (except lubricant) described in Table 1 were charged to a mixer-granulator (Diosna, 1 litre bowl, Pl/6) and mixed. Purified water was added to the powders with further mixing until a suitable wet mass was formed. The resultant granules were dried to appropriate moisture content ( ⁇ 2% w/w LOD) using a fluid bed dryer (Vector, MFL.01) with an inlet air temperature of 65°C. The dried granules were milled using an appropriately sized screen (1 mm, Quadro Comil U3).
  • composition variant (% w/w)
  • Concentration of SSF in the compositions was increased after Run 2 to allow viable processability during compression. Theoretically, this would reduce adhesion of material to tablet punches and dies (Pharmaceutical Powder Compaction Technology, edited by Goran Alderborn and Christer Nystrom, Informa Healthcare, New York, 2008). However, increasing level of lubricant also typically reduces rate of dissolution due to the hydrophobic nature of the lubricant.
  • Dissolution was determined according to the general procedure of the United States Pharmacopeia using Apparatus 2 with pH1.3 hydrochloric acid and sodium chloride buffered solution at 37°C ⁇ 0.5°C and stirrer speed of 50 rpm. At 15, 30 and 60 minutes dissolution media was withdrawn and the concentration of Formula (I) in solution was determined by UV spectroscopy at a wavelength of 311 nm against an external standard solution. Dissolution profiles are shown in Figure 1, the dissolution data is presented in
  • Example 2 Assessment of tablet punch filming of ten alternative tablet forms
  • Example 1 Ten different prototype tablets were prepared from a wet granulation formulation using methods well known to those skilled in the art. The composition and manufacturing process of each of these tablets is described in Example 1.
  • Example 3 Assessment of tablet water absorption of ten alternative tablet forms
  • Example 1 Ten different prototype tablets were prepared from a wet granulation formulation using methods well known to those skilled in the art. The composition and manufacturing process of each of these tablet compositions is described in Example 1.
  • Example 4 Assessment of dissolution performance of a further nineteen alternative tablet forms
  • Run 6 (Examples 1, 2 and 3) was selected for further development because, unlike other compositions, it showed a marked improvement in pH1.3 dissolution (Table 1), an improvement in punch filming (Table 7) and low water absorption (Table 8).
  • Formula (I) and the excipients described in Table 9 were charged to a mixer-granulator (Colette Gral 10) and mixed. Purified water (Ranging from 15% w/w to 45% w/w as set out in Table 9) was added to the powders with further mixing until a suitable wet mass was formed (ranging from approximately 3 to 14 mins) at 420 rpm.
  • the resultant granules were dried to appropriate moisture content ( ⁇ 2% LOD) using a fluid bed dryer (Aeromatic Strea 1) with an inlet air temperature of 80°C.
  • the dried granules were milled using an appropriately sized screen (1.4 mm, Quadro Comil U3). SSF was then added to the granules, which were then blended (Copley, Mobile Blender 7.5 litre drum) for 5 mins at 25 rpm before compressing into tablet cores using conventional tabletting equipment (Korch XL 100).
  • Dissolution was determined according to the general procedure of the United States Pharmacopeia using Apparatus 2 with pH1.3 hydrochloric acid and sodium chloride buffered solution at 37°C ⁇ 0.5°C and stirrer speed of 50 rpm. At 15, 30 and 60 minutes dissolution media was withdrawn and the concentration of Formula (I) in solution was determined by UV spectroscopy at a wavelength of 31 lnm against an external standard solution. Dissolution profiles are shown in Figure 2, the dissolution data is presented in Table 10. Table 10
  • Example 5 Assessment of chemical stability of a sixteen alternative tablet forms
  • Formula (I) and the excipients (except lubricant) described in Table 11 were charged to a mixer-granulator (Mi-Pro, 500 ml bowl) and mixed. Purified water was added (approximately 10 ml/min) to the powders with further mixing until a suitable wet mass was formed. The resultant granules were dried to
  • Total impurities were measured by injection of the prepared sample and standard solutions onto an LC system selected to ensure the separation of Formula (I) from organic impurities and excipients.
  • the chromatographic responses due to Formula (I) and organic impurities are measured on a UV detector at wavelength 245nm.
  • the response due to Formula (I) present in the sample was compared to that of a standard and its assay was calculated.
  • the level of organic impurities was calculated as %w/w. Equivalent response was assumed between Formula (I) and organic impurities.
  • samples were stored in a controlled environment for four weeks at 60°C and 80% relative humidity. After analysis, samples with SSF in their composition contained 0.99 ⁇ 0.36% (mean ⁇ standard deviation%) and samples with MgSt in their composition contained 1.93 ⁇ 1.34% (mean ⁇ standard deviation%).
  • Example 6 Assessment of dissolution performance when varying SSF concentration and inclusion of an alternative lubricant
  • composition variant (% w/w) (% w/w)
  • Dissolution was determined according to the general procedure of the United States Pharmacopeia using Apparatus 2 with pH6.8 phosphate buffered solution at 37°C ⁇ 0.5°C and stirrer speed of 75 rpm. At 15, 30, 45 and 60 minutes dissolution media was withdrawn and the concentration of Formula (I) in solution was determined by UV spectroscopy at a wavelength of 298 nm against an external standard solution. Dissolution results are shown in Figure 3 and the dissolution data is presented in Table 13.
  • Example 7 Assessment of tablets of Formula (I) prepared with different lubricants
  • the pharmaceutical composition comprises the following components (% w/w):
  • Composition A (°/ 0 Composition B (°/ 0 Composition C (% w/w) w/w) w/w)
  • Dissolution was determined according to the general procedure of the United States Pharmacopeia using Apparatus 2 with pH6.8 phosphate buffered solution at 37°C ⁇ 0.5°C and stirrer speed of 50 rpm. At 15, 30, and 60 minutes dissolution media was withdrawn and the concentration of Formula (I) in solution was determined by UV spectroscopy at a wavelength of 298nm against an external standard solution.
  • Composition C was selected for further study because, unlike other compositions, it (i) did not contain MgSt, which on average gave more impurities than SSF (Example 5); (ii) did not contain SSF, inclusion of which can affect extent of dissolution release (Figure 3); and (iii), demonstrated acceptable dissolution performance throughout the physiologically relevant pH range (Table 15).
  • Composition C 15 minutes 30 minutes 60 minutes
  • Example 8 Assessment of dissolution performance of ten alternative tablet formulations
  • compositions were prepared from a wet granulation using methods well known to those skilled in the art.
  • the composition of each of these tablets is qualitatively similar to Composition C (Example 7). Quantitative compositions are set out in Table 16.
  • composition API MgCC-3 Glydb Mannitol MCC SSG HPC
  • Formula (I) and the excipients (except lubricant) described in Table 16 were charged to a mixer-granulator (Diosna, 1 litre bowl, Pl/6) and mixed. Purified water was added (approximately 10 ml/min) to the powders with further mixing until a suitable wet mass was formed. The resultant granules were dried to appropriate moisture content ( ⁇ 2% w/w LOD) using a fluid bed dryer (Aeromatic Strea 1). The dried granules were milled using an appropriately sized screen (1.4 mm, Quadro Comil U3).
  • Lubricant was then added to the granules, which were then blended (WAB turbula) for 10 mins at 55 rpm.
  • the granules were then compressed into tablet cores (each core normalised to 80mg of formula 1) using conventional tabletting equipment (Riva Piccola (W.I.P) tablet press) at a normalised pressure of lOOMPa.
  • Example 9 Assessment of tablet punch filming of ten alternative tablet formulations
  • Example 8 Ten alternative prototype tablets were prepared from a wet granulation formulation using methods well known to those skilled in the art. The composition and manufacturing process of each of these tablets is described in Example 8. Material adhesion to tablet punch surfaces (described below as 'filming') is a well known tabletting process defect (Journal of Pharmaceutical Sciences, Vol. 93(2), 2004). Extent of filming was visually assessed for each formulation and reported in Table 19.
  • One alternative tablet formulation was prepared from a wet granulation using methods well known to those skilled in the art.
  • the composition of the tablet core is quantitatively similar to Composition C (Example 7) and a film coat was applied using a conventional film coating method to enhance the tablet appearance.
  • the quantitative composition of the tablet core formulation is presented in Table 20. Table 20
  • a film coat was applied using a propriety mixture of coating excipients, Opadry II Biege, supplied by Colorcon.
  • Formula (I) and the excipients (except lubricant) described in Table 20 were charged to a mixer-granulator (Gral 25) and mixed. Purified water was added (approximately 166 ml/min) to the powders with further mixing until a suitable wet mass was formed. The resultant granules were dried to appropriate moisture content ( ⁇ 2% w/w LOD) using a fluid bed dryer (Glatt 59P). The dried granules were milled using an appropriately sized screen (1.4 mm, Quadro Comil U3).
  • Lubricant was then added to the granules, which were then blended (Copley Mobile Blender, 7.5L container) for 5 mins at 25 rpm.
  • the granules were then compressed into tablet cores using conventional tabletting equipment (Riva Piccola-Nova, tablet press) to achieve a target compression weight of 375mg.
  • the tablet cores were over coated with a film coat using conventional pan coating equipment (O'Hara Labcoat II-X) to achieve a tablet weight gain of 3% w/w.
  • Dissolution was determined according to the general procedure of the United States Pharmacopeia using Apparatus 2 with both pH6.8 phosphate solution and pH1.3 hydrochloric acid and sodium chloride solution at 37°C ⁇ 0.5°C and stirrer speed of 50 rpm. At 15, 30 and 60 minutes dissolution media was withdrawn and the concentration of Formula (I) in solution was determined by UV spectroscopy at a wavelength of 311 nm (for pH 1.3 solution) or 298 nm (for pH 6.8 solution) against an external standard solution.

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PCT/GB2013/053356 2012-12-21 2013-12-19 Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide WO2014096828A1 (en)

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ES13821906T ES2742400T3 (es) 2012-12-21 2013-12-19 Formulación farmacéutica de N-[5-[2-(3,5-dimetoxifenil)etil]-2H-pirazol-3-il]-4-[(3R,5S)-3,5-dimetilpiperazin-1-il]benzamida
JP2015548757A JP6328138B2 (ja) 2012-12-21 2013-12-19 Ｎ−［５−［２−（３，５−ジメトキシフェニル）エチル］−２ｈ−ピラゾール−３−イル］−４−［（３ｒ，５ｓ）−３，５−ジメチルピペラジン−１−イル］ベンズアミドの医薬製剤
KR1020157019620A KR20150096787A (ko) 2012-12-21 2013-12-19 Ｎ-[5-[2-(3,5-디메톡시페닐)에틸]-2ｈ-피라졸-3-일]-4-[(3ｒ,5ｓ)-3,5-디메틸피페라진-1-일]벤즈아미드의 약학 제제
BR112015014200A BR112015014200A2 (pt) 2012-12-21 2013-12-19 formulação farmacêutica de n-[5-[2-(3,5-dimetoxi fenil) etil]-2h-pirazol-3-il]-4-[(3r,5s)-3,5-dimetil piperazin-1-il] benzamida
RU2015126345A RU2674978C2 (ru) 2012-12-21 2013-12-19 Фармацевтическая композиция N-[5-[2-(3,5-диметоксифенил)этил]-2H-пиразол-3-ил]-4-[(3R,5S)-3,5-диметилпиперазин-1-ил]бензамида
UAA201506048A UA115342C2 (uk) 2012-12-21 2013-12-19 Фармацевтична композиція, що містить n-[5-[2-(3,5-диметоксифеніл)етил]-2h-піразол-3-іл]-4-[(3r,5s)-3,5-диметилпіперазин-1-іл]бензамід
CN201380065855.6A CN104853750B (zh) 2012-12-21 2013-12-19 N-[5-[2-(3，5-二甲氧基苯基)乙基]-2h-吡唑-3-基]-4-[(3r，5s)-3，5-二甲基哌嗪-1-基]苯甲酰胺的医药配制品
MX2015008067A MX368670B (es) 2012-12-21 2013-12-19 Formulación farmacéutica de n-[5-[2-(3,5-dimetoxifenil)etil]-2h-pi razol-3-il]-4-[ (3r,5s)-3,5-dimetilpiperazin-1-il] benzamida.
AU2013366023A AU2013366023B2 (en) 2012-12-21 2013-12-19 Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide
CA2893480A CA2893480C (en) 2012-12-21 2013-12-19 Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide
EP13821906.8A EP2934494B1 (en) 2012-12-21 2013-12-19 Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide
SG11201504769WA SG11201504769WA (en) 2012-12-21 2013-12-19 Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide
CR20150320A CR20150320A (es) 2012-12-21 2015-06-17 Formulación farmacéutica de n-[5-[2-(3,5-dimetoxifenil) etil]-h-pirazol-3-il]-4-[(3r, 5s)-3,5-dimetilpiperazin-1-il]benzamida
PH12015501389A PH12015501389A1 (en) 2012-12-21 2015-06-17 Pharmaceutical formulation of n- [5-[2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide
IL239521A IL239521A0 (en) 2012-12-21 2015-06-18 Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-h2-pyrazol-3-yl]-4-[(3r,5s)]-3,5-dimethylpiperazin-1-yl] Benzamide
ZA2015/05197A ZA201505197B (en) 2012-12-21 2015-07-20 Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl] benzamide
HK16100256.1A HK1212229A1 (zh) 2012-12-21 2016-01-12 -二甲氧基苯基 乙基 -吡唑- -基 -二甲基哌嗪- -基 苯甲酰胺的醫藥配製品

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WO2024031226A1 (zh) * 2022-08-08 2024-02-15 无锡和誉生物医药科技有限公司 Fgfr抑制剂的药物组合物、多晶型物及其在药学上的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080153812A1 (en) * 2006-12-21 2008-06-26 Astrazeneca Ab Novel compounds
WO2012052757A1 (en) * 2010-10-20 2012-04-26 Astrazeneca Ab Tumour phenotype patient selection method

Family Cites Families (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB843940A (en) 1955-09-27 1960-08-10 Kodak Ltd Method of processing photographic silver halide emulsions containing colour couplers
BE667399A (zh) 1964-07-30 1965-11-16
JPS57150846A (en) 1981-03-13 1982-09-17 Konishiroku Photo Ind Co Ltd Photographic element
JPS63133152A (ja) 1986-11-26 1988-06-04 Konica Corp 新規なマゼンタカプラ−を含有するハロゲン化銀写真感光材料
JPH0467645A (ja) 1990-07-09 1992-03-03 Nec Kyushu Ltd バーンイン装置
US5292520A (en) * 1990-09-13 1994-03-08 Akzo N.V. Stabilized solid pharmaceutical composition containing acid addition salts of a basic drug and an alkaline stabilizer
JP2890065B2 (ja) 1990-11-10 1999-05-10 コニカ株式会社 ハロゲン化銀写真感光材料
JPH04184437A (ja) 1990-11-20 1992-07-01 Fuji Photo Film Co Ltd カラー画像形成方法及びハロゲン化銀カラー写真感光材料
JPH04292322A (ja) 1991-03-19 1992-10-16 Fujitsu Ltd ラック給排装置
JPH0511414A (ja) 1991-07-02 1993-01-22 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料
HU219131B (hu) 1991-10-18 2001-02-28 Monsanto Co. Módszer és fungicid készítmény növények torsgombabetegségének gátlására és a hatóanyagok
JPH07500116A (ja) 1992-03-26 1995-01-05 ダウエランコ 殺菌剤としてのｎ−複素環式ニトロアニリン
HRP921338B1 (en) 1992-10-02 2002-04-30 Monsanto Co Fungicides for the control of take-all disease of plants
TW240217B (zh) 1992-12-30 1995-02-11 Glaxo Group Ltd
JP3156026B2 (ja) 1993-12-27 2001-04-16 株式会社大塚製薬工場 ホスホン酸ジエステル誘導体
WO1996014843A2 (en) 1994-11-10 1996-05-23 Cor Therapeutics, Inc. Pharmaceutical pyrazole compositions useful as inhibitors of protein kinases
FR2745500B1 (fr) 1996-03-04 1998-04-03 Synthelabo Formulations pharmaceutiques a liberation prolongee contenant de la mizolastine
ATE443698T1 (de) 1996-12-23 2009-10-15 Bristol Myers Squibb Pharma Co Stickstoffhaltige heterocyclen als faktor xa- hemmer
CA2302438A1 (en) 1997-05-19 1998-11-26 Sugen, Inc. Heteroarylcarboxamide compounds active against protein tyrosine kinase related disorders
US6087381A (en) 1997-05-22 2000-07-11 G. D. Searle & Company Pyrazole derivatives as p38 kinase inhibitors
US6271237B1 (en) 1997-12-22 2001-08-07 Dupont Pharmaceuticals Company Nitrogen containing heteromatics with ortho-substituted P1s as factor Xa inhabitors
JP3310226B2 (ja) 1998-10-16 2002-08-05 松下電器産業株式会社 音声合成方法および装置
GB9823103D0 (en) 1998-10-23 1998-12-16 Pfizer Ltd Pharmaceutically active compounds
DE60017115T2 (de) 1999-02-10 2005-12-08 Mitsubishi Pharma Corp. Amid-derivate und deren medizinische verwendung
WO2000049001A2 (en) 1999-02-16 2000-08-24 E.I. Du Pont De Nemours And Company Phenoxy-, phenylthio-, phenylamino-, benzyloxy-, benzylthio- or benzylaminopyrimidine insectidices and acaricides
GEP20053476B (en) 1999-08-12 2005-03-25 Upjohn Co 3(5)-Amino-Pyrazole Derivatives, Process for Their Preparation and Their Use as Antitumor Agents
JP2003531103A (ja) 1999-08-12 2003-10-21 バーテックス ファーマシューティカルズ インコーポレイテッド ｃ−ＪＵＮＮ−末端キナーゼ（ＪＮＫ）および他のタンパク質キナーゼの阻害剤
ATE350044T1 (de) 1999-09-24 2007-01-15 Smithkline Beecham Corp Thrombopoietinmimetika
US20050209297A1 (en) 2000-08-31 2005-09-22 Pfizer Inc Pyrazole derivatives
US20040043904A1 (en) 2000-09-22 2004-03-04 Hiroshi Yamaguchi N-(4-pyrazolyl) amide derivatives, chemicals for agricultural and horticultural use, and usage of the same
EP1844766B1 (en) 2000-12-18 2012-04-18 Institute of Medicinal Molecular Design, Inc. Inhibitors against the production and release of inflammatory cytokines
US6878714B2 (en) 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
US6995162B2 (en) 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US6706711B2 (en) 2001-04-27 2004-03-16 Vertex Pharmaceuticals Incorporated Pyrazole derived kinase inhibitor
IS1935B (is) * 2002-03-19 2004-06-16 Actavis Group Hf. Fósínópríl lyfjasamsetning
TW200407112A (en) 2002-06-05 2004-05-16 Inst Med Molecular Design Inc Immunity-related protein kinase inhibitors
US20060111409A1 (en) 2002-06-05 2006-05-25 Susumu Muto Medicament for treatment of diabetes
WO2003103665A1 (ja) 2002-06-06 2003-12-18 株式会社医薬分子設計研究所 抗アレルギー薬
WO2004007472A1 (ja) 2002-07-10 2004-01-22 Ono Pharmaceutical Co., Ltd. Ｃｃｒ４アンタゴニストおよびその医薬用途
EP1542999A1 (en) 2002-08-01 2005-06-22 Pharmacia & Upjohn Company LLC 1h-pyrazole and 1h-pyrrole-azabicyclic compounds with alfa-7 nachr activity
ES2349532T3 (es) 2003-02-06 2011-01-04 Bristol-Myers Squibb Company Compuestos basados en tiazolilo útiles como inhibidores de cinasa.
US20040220170A1 (en) 2003-05-01 2004-11-04 Atkinson Robert N. Pyrazole-amides and sulfonamides as sodium channel modulators
ATE482200T1 (de) 2003-05-01 2010-10-15 Bristol Myers Squibb Co Als kinaseinhibitoren geeignete arylsubstituierte pyrazolamidverbindungen
US7115359B2 (en) 2003-07-25 2006-10-03 Konica Minolta Medical & Graphic, Inc. Photothermographic material
EP1664032B1 (en) 2003-08-21 2008-11-05 OSI Pharmaceuticals, Inc. N-substituted pyrazolyl-amidyl-benzimidazolyl c-kit inhibitors
US7432271B2 (en) 2003-09-02 2008-10-07 Bristol-Myers Squibb Company Pyrazolyl inhibitors of 15-lipoxygenase
US20050165031A1 (en) 2003-11-13 2005-07-28 Ambit Biosciences Corporation Urea derivatives as ABL modulators
US7671072B2 (en) 2003-11-26 2010-03-02 Pfizer Inc. Aminopyrazole derivatives as GSK-3 inhibitors
US7652146B2 (en) 2004-02-06 2010-01-26 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors
GB2411355B (en) * 2004-02-27 2006-02-22 Niche Generics Ltd Pharmaceutical composition
US7253204B2 (en) 2004-03-26 2007-08-07 Methylgene Inc. Inhibitors of histone deacetylase
WO2005105780A2 (en) 2004-04-28 2005-11-10 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of rock and other protein kinases
JO2787B1 (en) 2005-04-27 2014-03-15 امجين إنك, Alternative amide derivatives and methods of use
CN101273023A (zh) 2005-08-02 2008-09-24 Irm责任有限公司 作为蛋白激酶抑制剂的5-取代的噻唑-2-基氨基化合物和组合物
WO2007038979A1 (en) * 2005-09-22 2007-04-12 Swissco Development Ag Effervescent metformin composition and tablets and granules made therefrom
IS2385B (is) * 2006-02-10 2008-07-15 Actavis Group Hf. Klópidógrel bísúlfat lyfjasamsetningar
PL386051A1 (pl) * 2008-09-09 2010-03-15 Zakłady Farmaceutyczne POLPHARMA Spółka Akcyjna Stabilna doustna kompozycja farmaceutyczna zawierająca farmaceutycznie dopuszczalną sól kwsu [(E)-7-[4-(4-fluorofenylo)-6-izopropylo-2-[metylo(metylosulfonylo)amino]pirymidyn-5-ylo] (3R,5S)-3,5-dihydroksyhept-6-enowego
NZ595902A (en) * 2009-04-24 2014-10-31 Iceutica Pty Ltd Method for the production of commercial nanoparticle and microparticle powders
WO2010137855A2 (en) * 2009-05-27 2010-12-02 Dasan Medichem Co., Ltd. Multi-layer tablet comprising effervescent layer
JP2013501810A (ja) * 2009-08-12 2013-01-17 ヴァリーント インターナショナル（バルバドス）エスアールエル 医薬組成物
US20140179712A1 (en) 2012-12-21 2014-06-26 Astrazeneca Ab Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080153812A1 (en) * 2006-12-21 2008-06-26 Astrazeneca Ab Novel compounds
WO2008075068A2 (en) 2006-12-21 2008-06-26 Astrazeneca Ab Acylaminopyrazoles as fgfr inhibitors
WO2012052757A1 (en) * 2010-10-20 2012-04-26 Astrazeneca Ab Tumour phenotype patient selection method

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", 2005, AMERICAN PHARMACEUTICAL ASSOCIATION AND THE PHARMACEUTICAL PRESS
"Pharmaceutical Powder Compaction Technology", 2008, INFORMA HEALTHCARE
JAVAID ET AL., J. PHARM. SCI., vol. 61, no. 9, 1972, pages 1370 - 1373
JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 93, no. 2, 2004
KHATTAB, J. PHARM. PHARMACOL., vol. 45, 1992, pages 687 - 691
MUKHERJEE, FOOD CHEM. TOXICOL., vol. 35, 1997, pages 1177 - 1179
POWDER TECHNOLOGY, vol. 117, 2001, pages 3 - 39
POWDER TECHNOLOGY, vol. 88, 1996, pages 15 - 20
ROLLS, AM. J. CLIN. NUTR., vol. 53, 1991, pages 872 - 878
ZHANG J. ET AL.: "Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models", CLIN. CANCER RES., vol. 18, no. 24, 18 October 2012 (2012-10-18), pages 6658 - 6667, XP002720335 *

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